Breaking New Ground: Immune System Discovery Offers Potential Solution to Alzheimer’s

A groundbreaking study has shed new light on the relationship between the immune system and Alzheimer’s disease. Researchers at the University of Virginia School of Medicine have discovered that an immune molecule called STING plays a crucial role in driving the formation of amyloid plaques and tau tangles, hallmarks of Alzheimer’s.

The study found that blocking STING activity in lab mice protected them from mental decline, suggesting a promising new target for developing treatments. This breakthrough has far-reaching implications for understanding and treating not only Alzheimer’s but also other neurodegenerative diseases like Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and dementia.

“The findings demonstrate that the DNA damage that naturally accumulates during aging triggers STING-mediated brain inflammation and neuronal damage in Alzheimer’s disease,” said researcher John Lukens, PhD. “These results help to explain why aging is associated with increased Alzheimer’s risk and uncover a novel pathway to target in the treatment of neurodegenerative diseases.”

The study, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, involved a team of researchers from UVA’s Department of Neuroscience and Center for Brain Immunology and Glia (BIG Center). They found that removing STING dampened microglial activation around amyloid plaques, protected nearby neurons from damage, and improved memory function in Alzheimer’s model mice.

The discovery of STING as a key player in the development of neurodegenerative diseases opens new doors for research into potential treatments. While much more work is needed to translate these findings into effective therapies, this breakthrough has sparked hope among researchers and patients alike.

“Our hope is that this work moves us close to finding safer and more effective ways to protect the aging brain,” said Lukens. “Shedding light on how STING contributes to that damage may help us target similar molecules and ultimately develop effective disease-modifying treatments.”

Research has discovered that men who carry a common genetic variant are twice as likely to develop dementia in their lifetime compared to women. This groundbreaking study, published in Neurology, used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial to investigate whether people with variants in the haemochromatosis (HFE) gene might be at increased risk of dementia.

One in three people carry one copy of the H63D variant, while one in 36 carry two copies. Having just one copy of this gene variant does not impact someone’s health or increase their risk of dementia. However, having two copies of the variant more than doubled the risk of dementia in men, but not women.

The researchers emphasize that the genetic variant itself cannot be changed, but the brain pathways affected by it could potentially be treated if we understood more about it. Further research is needed to investigate why this genetic variant increased the risk of dementia for males but not females.

The findings suggest that perhaps testing for the HFE gene could be offered to men more broadly, considering its routine testing in most Western countries, including Australia, when assessing people for haemochromatosis – a disorder that causes the body to absorb too much iron. The study found no direct link between iron levels in the blood and increased dementia risk in affected men.

This points to other mechanisms at play, possibly involving the increased risk of brain injury from inflammation and cell damage in the body. Understanding why men with the double H63D variant are at higher risk could pave the way for more personalized approaches to prevention and treatment.

The ASPREE trial was a groundbreaking study that created a treasure trove of healthy ageing data, which has underpinned a wealth of research studies. This collaboration between Curtin University, Monash University, The University of Melbourne, The Royal Children’s Hospital, Murdoch Children’s Research Institute, and Fiona Stanley Hospital demonstrates the importance of diverse Australian research groups working together to improve health outcomes for people around the world.

The implications of this study are significant, considering that more than 400,000 Australians are currently living with dementia, with around a third of those being men. This discovery could lead to improved outcomes for people at risk of developing dementia and ultimately contribute to a better understanding of these progressive diseases.

The APOE gene is a major genetic risk factor for Alzheimer’s disease, with three different versions: APOE2, APOE3, and APOE4. While APOE4 increases the risk of developing Alzheimer’s, APOE2 is associated with a lower risk. However, how these isoforms lead to strikingly different risk profiles is poorly understood.

A recent study published in Nature Communications offers clues into how APOE isoforms differentially affect human microglia function in Alzheimer’s disease. The study, led by Dr. Sarah Marzi and Dr. Kitty Murphy at the UK Dementia Research Institute at King’s College London and the Department of Basic and Clinical Neuroscience, underscores the need for new targeted interventions based on APOE genotypes.

The researchers developed a human “xenotransplantation model,” where human microglia were grown from stem cells, manipulated to express different APOE versions, then transplanted into the brains of mice that had developed a buildup of amyloid plaques. The microglia were then isolated and analyzed for their gene expression (using transcriptomics) and chromatin accessibility.

The study uncovered widespread changes to the transcriptomic and chromatin landscape of microglia, dependent on the APOE isoform expressed. The largest differences were observed when comparing the APOE2 and APOE4 microglia.

In APOE4 microglia, researchers saw an increase in the production of cytokines, signaling molecules involved in immune regulation. They also observed diminished capacity for the microglia to migrate and shift into protective states. Furthermore, the microglia became less effective in phagocytosis, a process by which they digest and clear up particles such as debris and pathogens.

Conversely, APOE2 microglia showed increased expression of various genes that increase microglia proliferation and migration, and a decreased inflammatory immune response. Additionally, APOE2 microglia showed increased DNA-binding of the vitamin D receptor. Low levels of vitamin D have been associated with a higher incidence of Alzheimer’s.

The study highlights that microglia responses to amyloid pathology differ significantly across APOE versions. This finding underscores that considering the interplay between genetic risk factors and microglial states is critical in disease progression. The study also highlights the potential role of the vitamin D receptor, providing new avenues for therapeutic exploration.

Dr. Sarah Marzi, Senior Lecturer in Neuroscience at King’s College London and lead author of the study, said: “Our findings emphasize that there is a complex interplay between genetic, epigenetic, and environmental factors that influence microglial responses in Alzheimer’s disease. We found remarkable differences when comparing microglia expressing different isoforms of the same gene. Our research suggests that microglia expressing the risk-increasing APOE4 variant are not as effective at mounting protective microglial functions, including cell migration, phagocytosis and anti-inflammatory signaling. This underscores the need for targeted interventions based on APOE genotype.”